The CFTA method: A reliable procedure for the determination of the absolute configuration of chiral primary amines by 1H NMR spectroscopic analysis

Article abstract of DOI:10.1002/anie.200600157

Surprisingly stable anti-periplanar conformers of CFTA amides form the basis of a new and very reliable method for determining the absolute configuration of chiral primary amines by ¹H NMR spectroscopy (see picture). CFTA = α-cyano-α-fluoro-p-tolylacetic acid. (Chemical Equation Presented).

Full text of DOI:10.1002/anie.200600157

Angewandte
Chemie
Structure Elucidation
DOI: 10.1002/anie.200600157
The CFTA Method: A Reliable Procedure for the
Determination of the Absolute Configuration of
1
Chiral Primary Amines by H NMR Spectroscopic
Analysis**
Yoshio Takeuchi,* Masaru Segawa, Hidehito Fujisawa,
Kenji Omata, Siegfried N. Lodwig, and
Clifford J. Unkefer
Methods for the determination of the absolute configuration
of chiral molecules are indispensable in modern organic
chemistry, especially in asymmetric synthesis and in studies of
[
1]
the structures of complex natural products. Although the
[
2]
modified Mosher method with a-methoxy-a-trifluorome-
[
3]
thylphenylacetic acid (MTPA, 1) is often employed for this
purpose, many cases have been identified in which the MTPA
procedure can not be applied, either because of the low
[
4]
reactivity of MTPA chloride (2) or because of the number of
[
5]
complex conformers observed in the MTPA derivatives. To
overcome these limitations, we developed a-cyano-a-fluoro-
phenylacetic acid (CFPA, 3), in which the fluorine atom is
[
*] Prof. Dr. Y. Takeuchi, M. Segawa, H. Fujisawa
Faculty of Pharmaceutical Sciences
University of Toyama
Sugitani, Toyama 930-0194 (Japan)
Fax: (+81)76-434-5053
E-mail: takeuchi@pha.u-toyama.ac.jp
Dr. K. Omata
Department of Chemistry
Graduate School of Science, Tohoku University
Aramaki, Aoba-ku, Sendai 980-8578 (Japan)
Dr. S. N. Lodwig, Dr. C. J. Unkefer
National Stable Isotope Resource
Bioscience Division, MSE529
Los Alamos National Laboratory
Los Alamos, NM 87544 (USA)
[
**] The authors are grateful to Dr. K. Kabuto of Tohoku University for his
helpful suggestion. This work was partially supported by the
National Stable Isotope Resource at Los Alamos (NIH 5P41
EB002166). CFTA=a-cyano-a-fluoro-p-tolylacetic acid.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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4617

Communications
located on the stereogenic center. We found that CFPA
chloride (4) reacts with nucleophiles 500 times faster than
MTPA chloride (2), and even undergoes condensation with
[
6]
hindered nucleophiles, such as pinacolyl alcohol.
The phenyl hydrogen atoms of CFPA give rise to a
1
complex multiplet in the H NMR spectrum, which can often
1
complicate the analysis of the H NMR spectra of substrates
with aromatic substituents. We therefore decided to search for
a derivatizing agent with more readily distinguishable aro-
matic proton signals to simplify the assignment of proton
[
7]
signals to the derivatized diastereomers. This approach led
to our development of a-cyano-a-fluoro-p-tolylacetic acid
[
8]
(
CFTA, 5; T o =l tolyl), a reagent that can be used in the
determination of the absolute configuration of chiral carbi-
[
9]
nols, even those with two essentially identical substitu-
[
10]
ents.
Herein, we report that the CFTA method is also
reliably applicable to the determination of the absolute
configuration of various chiral amine compounds.
We measured the chemical-shift difference, DdH
[
11]
(
(
d Àd ), for corresponding protons of the diastereomeric
S
R
S)- and (R)-CFTA amides of chiral primary amines 7–14 of
[
2]
known absolute configuration (Scheme 1). All proton
signals for the amine residue were assigned for both the (S)-
and (R)-CFTA diastereomers by means of COSY and other
NMR spectroscopic techniques. Thus, a Dd value was readily
H
obtained for each hydrogen atom of the diastereomers.
The CFTA–amide plane is defined as the plane with an
[
12]
all-anti
Scheme 2). When the CFTA amides are depicted in a
(FÀC)À(C=O)À(NÀH)À(CÀH)
conformation
(
manner such that the two substituents at the stereogenic
center adjacent to the N atom are in the plane of the page
(
which is perpendicular to the CFTA–amide plane) and the
a hydrogen atom is coming out of the plane of the page, the
hydrogen atoms with negative Dd values are invariably on
H
the left-hand side of the CFTA–amide plane and those with
positive Dd values are on the right-hand side of the CFTA–
H
amide plane (Scheme 1). In general, greater Dd values were
H
observed for the CFTA amides than for the MTPA amides.
Thus, the CFTA method enables the determination of the
1
absolute configuration of chiral amines by H NMR spectros-
copy much more readily and accurately than the method with
MTPA.
To investigate the scope and limitations of the CFTA
method, we applied our procedure to the multiply labeled
amino acid derivatives 15 and 16. From the Dd values
Scheme 1. DdH or Dd values for CFTA amide diastereomers of chiral
amines 7–16.
D
1
2
obtained by H and H NMR spectroscopy, we found that
both 15 and 16 have the S absolute configuration, as was
expected from the synthetic route used for their prepara-
hand side in an extended Newman projection, in which the
amide linkage is omitted for convenience. Conformational
arguments can be used to explain the algebraic signs of the
Dd values. In the case of the (S)-CFTA diastereomer, the
[
13]
tion. X-ray analysis of the CFTA amide of15 confirmed the
[
14]
S configuration for this derivative.
The signs of Dd on each side of the CFTA–amide plane
signals for the hydrogen atoms of the R group should always
R
were opposite for the CFTA amides to those observed for the
be shifted upfield as a result of the anisotropic shielding of the
aromatic ring. In contrast, for the R diastereomer, the hydro-
[
9]
CFTA esters and also opposite to those observed with
MTPA amides. Therefore, we propose that the stable
conformation for the amides is that in which the CÀF bond
occupies an anti-periplanar position with respect to the C=O
gen atoms of the R group are shielded, and these signals
S
should therefore appear upfield. Thus, the Dd values for the
protons on the left-hand side of the CFTA–amide plane
should be negative and those for the protons on the right-
bond (Scheme 2), in contrast to the syn-periplanar conforma-
tion that is favored in the case of the CFTA esters. The amides hand side of the plane should be positive. This conformation
of the chiral amines R R CHNH can be viewed from the left- was supported by X-ray crystallographic analysis of the CFTA
S
R
2
4
618
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Chemie
Sasaki, K. Omata, C. Kabuto, K. Kabuto, Y. Takeuchi, Tetrahe-
dron: Asymmetry 2004, 15, 555; d) (S)- and (R)-CFTA-Cl are
both commercially available from Kanto Denka Kogyo Co., Ltd.
9] T. Takahashi, A. Fukushima, Y. Tanaka, Y. Takeuchi, K. Kabuto,
C. Kabuto, Chem. Commun. 2000, 787.
[
[
[
10] Y. Takeuchi, H. Fujisawa, R. Noyori, Org. Lett. 2004, 6, 4607.
11] The Dd values are defined as d Àd , in which d and d are the
S
R
S
R
chemical shifts of the corresponding protons in the (S)- and (R)-
CFTA amides, respectively.
[
12] a) S. K. Latypov, J. M. Seco, E. Quiæoµ, R. Riguera, J. Org.
Chem. 1995, 60, 1538; b) C. R. S. Briggs, D. OꢀHagan, J. A. K.
Howard, D. S. Yufit, J. Fluorine Chem. 2003, 119, 9.
[
13] S. N. Lodwig, C. J. Unkefer, J. Labelled Compd. Radiopharm.
1998, XLI, 983; see also the Supporting Information.
[
14] CCDC-291185 and CCDC-291186 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
Scheme 2. Conformations of (S)- and (R)-CFTA amides of chiral
primary amines R R CHNH .
S
R
2
[
8a]
amide of 1-phenylethylamine
and ab initio calculations
(
GAUSSIAN98, RHF/6-31 + G*) of the CFPA amide of Val-
[
8b]
OMe as a similar molecule.
In summary, we have presented the CFTA method as a
new and reliable procedure for the determination of the
absolute configuration of chiral amines. This method has
important advantages over other conceptually similar proce-
dures available because of the very high reactivity of the
[
6]
agent and because the CÀF bond at the stereocenter exerts
[
12b]
strong conformational control on the amides.
For these
reasons we feel this method should be widely applicable.
Received: January 14, 2006
Published online: June 21, 2006
Keywords: CFTA diastereomers · configuration determination ·
.
NMR spectroscopy · reactivity
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